This invention relates to the treatment of hyperproliferative diseases, such as cancers, in mammals using benzazepine derivatives of formula I, as defined below. The compounds of formula I are described in U.S. Pat. Nos. 5,618,808, and 5,618,811, both of which issued Apr. 8, 1997 and both of which are incorporated herein by reference in their entirety. These references describe benzazepine derivatives as cholecystokinin (CCK) receptor antagonists useful in the treatment of certain disorders involving the central nervous system (CNS).
A cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype. It has been shown that certain tyrosine kinases may be mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Furthermore, the overexpression of a ligand for a tyrosine kinase receptor may result in an increase in the activation state of the receptor, resulting in proliferation of the tumor cells or endothelial cells. Thus, it is believed that the growth of mammalian cancer cells can be selectively inhibited by reducing tyrosine kinase activity.
Polypeptide growth factors, such as vascular endothelial growth factor (VEGF) having a high affinity to the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor, have been associated with the proliferation of endothelial cells and more particularly vasculogenesis and angiogenesis. See PCT international application publication number WO 95/21613 (published Aug. 17, 1995). A significant body of evidence has been put forth detailing the importance of VEGF in the formation of new blood vessels (angiogenesis). It has also been noted that new blood vessel formation is crucial in supplying and maintaining the physiological conditions and nutrients necessary for tumor growth and metastasis. It has been shown that both VEGF receptor subtypes appear to be over expressed in proliferating endothelial cells located in near proximity to tumor cells in vivo. At the molecular level, intracellular portions of both FLT-1 and FLK-1 contain functional tyrosine kinase domains. Kinase activities depend on high affinity to, and interaction with, VEGF. Such interaction results in the autophosphorylation of the receptors and ultimately in endothelial cell proliferation. High affinity VEGF binding and the resulting functional effects appear to depend on the presence of specific heparin sulfate proteoglycans (VEGF glyceptor) associated with the extracellular matrix of endothelial cells. This supposition is supported by the ability of exogenous levels of heparin to inhibit VEGF induced endothelial cell proliferation by acting as a sink for secreted VEGF. By inhibiting the binding of VEGF to VEGF glyceptor (GAG), phosphorylation of tyrosine (kinase) is modulated. Agents, such as the compounds of the present invention, which are capable of modulating the KDR/FLK-1 receptor, may be used to treat disorders related to vasculogenesis or angiogenesis. Such disorders include, but are not limited to, diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.